Insulin Therapy and Improved Outcome in the Intensive Care Unit—Beyond Lowering of Glycemia
Authors: L. Langouche, I. Vanhorebeek, D. Vlasselaers, S. Vander Perre, P.J. Wouters, K. Skogstrand, T.K. Hansen, G. Van den Berghe
Journal: Journal of the American Society of Nephrology (2006)

In uncontrolled observations it had been shown that hyperglycemia increases morbidity and mortality in critically ill patients even in the absence of diabetes (1–3). Furthermore, mainly in diabetic patients, the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study had shown improved short-term and long-term outcome from a regimen comprising strict glycemia control using infusion of glucose and insulin in patients with acute myocardial infarction as compared with conventional glycemia control (4, 5). The same protocol has been tried in stroke, so far without definite results (6). It is true that the beneficial effect on outcome after myocardial infarction could not be reproduced in the DIGAMI-2 study (7), presumably because coronary care has improved in the meantime and because the study may have been underpowered. Five years ago van den Berghe et al. (8) reported the results of a prospective, randomized, controlled study of 1548 patients in a surgical intensive care unit (ICU) to address the hypothesis that hyperglycemia or relative insulin deficiency (or both) during critical illness predisposed patients to complications such as severe infections, polyneuropathy, multiple organ failure including acute renal failure (9), and death. Patients were randomly assigned to intensive or conventional insulin therapy. In the intensive treatment group patients received an insulin infusion once the blood glucose concentration exceeded 110 mg/dl to maintain blood glucose within a range of 80 to 110 mg/dl, the maximal dose of insulin being 50 IU/h. In the conventional treatment group patients were started on insulin treatment once blood glucose concentration exceeded 215 mg/dl. This regimen achieved morning blood glucose concentrations of 103 ± 19 mg/dl in the intensive treatment group and 153 ± 33 mg/dl in the conventional treatment group. Death rate during intensive care was 4.6% in the intensive treatment versus 8.0% in the conventional treatment groups and in-hospital death for patients receiving intensive care for >5 d was 16.6% with intensive versus 26.3% in conventional treatment. The main features were less multiorgan failure with sepsis as well as—of particular interest to the nephrologists—less acute renal failure in the intensive treatment group (dialysis 4.8% in the intensive versus 8.2%in the conventional treatment group). These data in a surgical ICU might not necessarily apply to a medical ICU. To address this issue the same authors recently studied 1200 patients of a medical ICU. The data showed that intensive insulin therapy failed to reduce in-hospital mortality significantly (37.3% in the intensive treatment group versus 40.0% in the conventional treatment group). Nevertheless, in this study morbidity was again significantly reduced by preventing newly acquired kidney injury—confirming previous results of others (10)—and by accelerating the weaning from mechanical ventilation and discharge from the ICU and the hospital, respectively (11). These impressive studies left open the question whether it was glycemia control or delivery of insulin that provided the benefit and similarly raised the issue of which target organ function was involved in improving outcome. In the study discussed here, the same authors now addressed the hypothesis that organ failure and septicaemia were the result of an excessive inflammatory response to infection and injury with inappropriate endothelial cell activation playing a central role by compromising the microcirculation, inducing hypoxia and causing organ failure (8). They further hypothesized that during critical illness provision of insulin protected the endothelium. These hypotheses were examined in a preplanned subanalysis of the first of the above studies (8). What were the effects of intensive insulin therapy? Patients with intensive insulin treatment had lower C-reactive protein concentrations, had a lesser increase of the concentration of intercellular adhesion molecule-1 (ICAM-1) but not of E-selectin, had transiently (day 5) lower IL-10 concentrations, and tended to have lower IL-6 concentrations. To carry this one step further, the authors evaluated the gene and protein expression of the nitric oxide synthase (NOS) family in the livers and muscles of those patients who had died. nNOS gene as well as eNOS gene expression was unaffected by intensive insulin treatment, but iNOS gene expression was significantly lowered by insulin treatment both in the liver and in skeletal muscle. Furthermore, intensive insulin treatment tended to lower phosphorylated inhibitor of NFκB (IκB) in the liver, pointing to less activation of this central proinflammatory switch. Finally, serum NO (nitrate plus nitrite) was similarly elevated in the two groups on admission, but decreased on day 7 on intensive insulin treatment. A pathogenic role of NO is suggested by the observation that NO concentrations were higher in patients who did not survive. Interestingly, concentrations were also higher in patients who developed acute renal failure. The argument can be raised that hyperglycemia is a proinflammatory agent and insulin is an anti-inflammatory agent (12). The proinflammatory effect of hyperglycemia is linked to increased generation of reactive oxygen species (ROS) (13) among others by inducing mitochondrial abnormalities in the liver, which are prevented by insulin infusion (14). Even an oral glucose load that raises blood glucose but fails to cause hyperglycemia increases generation of ROS (15). This risk may be aggravated if the concentration of the antagonistic agent insulin is low (16). One important consequence of increased ROS generation is scavenging of NO by ROS, thus reducing its availability in the microcirculation and compromising the function of the microcirculation. The anti-inflammatory actions of insulin are mediated through three different signal pathways: NFκB, activator protein-1 (AP1), and early growth response-1 (EGR-1) (13, 17). Genes regulated by these transcription factors code for molecules that include proteins involved in the above inflammatory reaction. The proinflammatory action of hyperglycemia is antagonized by insulin, which suppresses the generation of ROS by interfering with the expression of p47phox, a constituent of NAD(P)H oxidase, one of the pathways of generating ROS (17, 18). Further beneficial effects of insulin, important for antagonizing the microcirculatory disturbance and the ensuing predisposition to organ damage, are increased NO release with improved vasodilatation and inhibition of platelet aggregation (19, 20). What are the implications of the study of Langouche et al. (21)? On the one hand, markers of the inflammatory response and predictors of target organ damage, including acute renal failure, may emerge from these results, e.g., plasma NO (NO2 + NO3). Furthermore, the case for using intensive insulin administration in critically ill patients in the medical ICU gets ever stronger (10, 11), despite the undoubted serious logistic problems posed by this intervention, which certainly is not without hazard in the absence of rigorous quality control. This study investigating intensive insulin infusion adds to what has already been documented in other settings, such as during cardiac surgery (22), management of the patient with burns (23), or with myocardial infarction (18).